JP2005531563A - Antitumor polycyclic carboxamide - Google Patents

Abstract

This invention relates to polycyclic carboxamide compounds of the formula I: with cytotoxicity, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment and/or prophylaxis of cellular proliferative disorders such as cancer.

Description

  The present invention relates to a novel class of cytotoxic polycyclic carboxamide compounds, methods for their formulation, pharmaceutical compositions containing them, and their use in therapy, particularly for the treatment of cell proliferative diseases such as cancer and / Or for use in prevention.

BACKGROUND OF THE INVENTION Compounds containing polycyclic chromophores with mobile cationic side chains have been known to exhibit cytotoxic effects and have utility as anticancer agents.

Tricyclic chromophores exhibiting cytotoxic activity are benzoisoquinolinediones (eg, amonafide, 1 ; Asbury et al., 1998; Leaf et al., 1997), acridine-4-carboxamide (acridine-4- carboxamides) (eg, DACA, 2 ; Atwell et al., 1987; Baguley et al., 1995; US Pat. No. 4,590,277) and anthraquinones (eg, mitoxantrone, 3 ; Koller et al., 1999).

Tetracyclic chromophores having cytotoxic activity include anthrapyrazoles (eg, losoxantrone, 4 ; Diab et al., 1999; Judson, 1992), indeno [2,1-c] quinoline-7- ON (eg, TAS-103, 5 ; Utsugi et al., 1996), benzophenazines (eg, XR-11576, 6 ; Vicker et al., 2002), azonafides (eg, 7; Sami et al., 1996), imidazoacridinones (eg, 8 ; Cholody et al., 1996), pyrimido [5,6,1-de] acridine (eg, 9 ; Antonini et al., 1995), Benzo [e] pyridio [4,3-b] indoles (eg, intoplicine, 10 ; Riou et al., 1993), indeno [1,2-b] quinolines (eg, 11 , Deady et al., 1997) and benzo [e] perimidine (eg, 12 , Stefanska et al., 1993).

Many compounds are effective cytotoxins and anticancer agents when two such chromophores are joined by a mobile chain. For example, bis (naphthalimide) DMP840, 13 , has been clinically evaluated (Thompson et al., 1998), bis (imidazoacridones) (eg WMC-26, 14 ; Cholody etal. 1995) and bis (bis (phenazines) (eg, XR 5944, 15 ; Gamet et al., 2001; Stewart et al., 2001) are considered clinical trials.

  From the publications referenced above, it can be seen that these compounds have a wide variety of different structures. These compounds are believed to be active as anticancer agents, primarily through their activity of inhibiting the topoisomerase enzyme. However, the relationship between structure and ability to inhibit the topoisomerase enzyme and its potential usefulness as an anti-cancer agent in vivo is not yet well defined and does not allow the predictions made for activity to be made. In view of the potential usefulness of such compounds, further classification of these compounds is required.

  The present invention relates to amide- (and thioamide) derivatives of benzo [b] [1,6] naphthyridin-1 (2H) -one, their synthesis, and their use in cancer therapy. Benzo [b] [1,6] naphthyridin-1 (2H) -one chromophore (Deady and Rodemann, 2001) and N2- and carbon-substituted analogs (Asherson and Young, 1977; Khattab, 1996; Meth-Cohn, 1987 Rivalle and Bisagni, 1980) is known to contain 6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (Deady and Rodemann, 2001) Yes. Dibenzo [b, h] [1,6] naphthyridin-6 (5H) -one has also been reported (Asherson and Young, 1977; Vijayalakshmi and Rajendran, 1994). However, these reports relate only to the synthesis of the compounds.

  Reference is made herein to a number of prior art documents, which constitute an acknowledgment that these documents do not form part of the common general knowledge of the art in Australia or other countries. It will be clearly understood that

  We have synthesized and evaluated a novel series of carboxamides that bind compounds based on benzo [b] [1,6] naphthyridin-1 (2H) -one. The series differed from previous acridine based compounds in that they incorporated a lactam or thiolactam functional group into one of the outer rings.

  Representative examples of these compounds have cytotoxicity and utility as anticancer agents.

｛式中、
記される位置番号は、上で図示される順序を指し、そして１以上のＷ及び１以上のＺは、１の環炭素と結合するか、又は３、４、及び６〜１０位のいずれかの位置で複数の環炭素と結合し、
ここで、
Ｑは、Ｏ又はＳであり；
Ｗは、Ｃ(＝Ｑ)ＮＲ-Ｍ-(ＣＨ₂)_mＲ¹
(基中、
Ｍは、ＣＨＪ又はＧであり、
Ｒは、Ｈ又は場合により置換されるＣ_1-4アルキル基であり、
Ｊは、Ｈ又は場合により置換されるＣ₁-Ｃ₆アルキル基であり、
Ｇは、場合により置換される完全飽和若しくは部分的に不飽和な炭素環若しくは複素環、又は芳香族炭素環若しくは複素環であり、
Ｒ¹は、Ｃ(＝ＮＲ²)ＮＨ₂、ＮＨＣ(＝ＮＲ³)ＮＨ₂、又はＮＲ⁴Ｒ⁵であり、
ここで、
Ｒ²及びＲ³の各々は、独立してＨ又は場合により置換されるＣ_1-4アルキル基であり、
Ｒ⁴及びＲ⁵は、独立してＨ又は場合により置換されるＣ_1-4アルキル基であり、或いは、Ｒ⁴及びＲ⁵は、それらが結合する窒素原子と一緒になって、場合により置換される飽和又は不飽和複素環基を形成し、そして
ｍは、０〜６の整数である。)であり；
Ｙは、Ｈ、Ｃ_1-6アルキル又は(ＣＨ₂)_n-Ｘ-(ＣＨ₂)_pＵ
(基中、
Ｘは、ＣＨ_2、Ｃ＝Ｏ、ＣＨ＝ＣＨ、Ｏ、Ｓ、ＮＲ又はＧであり、
ｎ及びｐは、０〜６の整数であり、かつ
Ｕは、Ｈ、ＣＦ₃、ハロ、ＮＲ⁴Ｒ⁵、⁺ＮＲＲ⁴Ｒ⁵、シアノ、Ｃ(＝Ｏ)ＮＲ⁴Ｒ⁵、ＯＲ⁴、ＣＯ₂Ｒ⁴、Ｇ、ＮＲ⁴Ｇ、又はＯＧである)であり；；そして
Ｚは、Ｈ、ハロ、ＯＨ、ＣＯ₂Ｈ、ＣＯ₂Ｒ⁴、ＳＯ₂Ｒ⁴、ＮＲ⁴Ｒ⁵、ニトロ、シアノ、Ｃ_1-6アルキル、Ｃ_1-6ハロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、Ｃ_1-6アミノアルキル、Ｃ_1-6アミノアルコキシ、又はＣＨ官能基を置換するアザ官能基、又は６-７、７-８、若しくは８-９位を架橋し、その結果さらに５〜６員環の融合炭素環又は複素環を形成する炭素又は炭素/窒素骨格である｝で表される化合物、又は医薬として許容される塩、Ｎ-オキシド、水和物、溶媒和化合物、医薬として許容される誘導体、プロドラッグ、互変異性体及び/又はその異性体を提供する。 SUMMARY OF THE INVENTION According to a first aspect, the present invention provides the following formula I:

{Where,
The position numbers noted refer to the order illustrated above, and one or more W and one or more Z are bonded to one ring carbon or are in any of the 3, 4, and 6-10 positions. Bond to multiple ring carbons at the position
here,
Q is O or S;
W is C (= Q) NR-M- (CH ₂ ) _m R ¹
(In the group,
M is CHJ or G;
R is H or an optionally substituted C _1-4 alkyl group;
J is H or an optionally substituted C ₁ -C ₆ alkyl group;
G is an optionally substituted fully saturated or partially unsaturated carbocyclic or heterocyclic ring, or an aromatic carbocyclic or heterocyclic ring;
R ¹ is C (= NR ² ) NH ₂ , NHC (= NR ³ ) NH ₂ , or NR ⁴ R ⁵ ;
here,
Each of R ² and R ³ is independently H or an optionally substituted C _1-4 alkyl group;
R ⁴ and R ⁵ are independently H or an optionally substituted C _1-4 alkyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are optionally substituted Forming a saturated or unsaturated heterocyclic group, and
m is an integer of 0-6. );
Y is H, C _1-6 alkyl or (CH ₂ ) _n —X— (CH ₂ ) _p U
(In the group,
X is CH2 _, C = O, CH = CH, O, S, NR or G;
n and p are integers from 0 to 6, and
U is H, CF ₃ , halo, NR ⁴ R ⁵ , ⁺ NRR ⁴ R ⁵ , cyano, C (═O) NR ⁴ R ⁵ , OR ⁴ , CO ₂ R ⁴ , G, NR ⁴ G, or OG Is;); and
Z is H, halo, OH, CO ₂ H, CO ₂ R ⁴ , SO ₂ R ⁴ , NR ⁴ R ⁵ , nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, A C _1-6 haloalkoxy, a C _1-6 aminoalkyl, a C _1-6 aminoalkoxy, or an aza functional group that replaces the CH functional group, or the 6-7, 7-8, or 8-9 position, As a result, the compound is a carbon or carbon / nitrogen skeleton that forms a 5- or 6-membered fused carbocyclic or heterocyclic ring, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvent Japanese compounds, pharmaceutically acceptable derivatives, prodrugs, tautomers and / or isomers thereof are provided.

The optional substituents for R, R ² , R ³ , R ⁴ , and R ⁵ are preferably one or more OH or NH ₂ groups, and the optional substituent for J is one or more OH, OMe, NH ₂ , NHMe or NMe ₂ group. Preferred optional substituents for G are one or more of halo, OH, CO ₂ H, NR ⁴ R ⁵ , NRSO ₂ R, SO ₂ NR ⁴ R ⁵ , nitro, cyano, C _1-6 alkyl, C _1-6 Haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 aminoalkyl, C _1-6 aminoalkoxy or B (OR ⁶ ) (OR ⁷ ) {wherein R ⁶ and R ⁷ are independently Hydrogen or optionally substituted C _1-4 alkyl groups, or together with the O and B atoms to which they are attached, optionally substituted or fully saturated, or partially unsaturated heterocycles Is formed}.

Preferably Q is O; W is CONH (CH ₂ ) ₂ N (CH ₃ ) ₂ or CONHCH (CH ₃ ) CH ₂ N (CH ₃ ) ₂ ; Y is methyl, butyl or methoxy-substituted phenyl Yes; Z is H, Cl, methyl or methoxy.

  Particularly preferred compounds are N- [2- (dimethylamino) ethyl] -2,6-dimethyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide or pharmaceutically acceptable Their salts or N-oxides.

｛式中、
式IIにおいて１以上のＷ及び１以上のＺ、並びに式IIIにおいて１以上のＺ及びＣ(＝Ｑ)ＮＲは、環炭素の一つ又は３、４、及び６〜１０位のいずれかの複数の環炭素に結合し、
ここで、
Ｑ、Ｒ、Ｗ、Ｙ、及びＺは、式Ｉに定義されるとおりであり；
ｘは、２〜４の整数であり、かつ
Ｌは、結合価ｘのリンカー基である｝で表される化合物、又はその医薬として許容される塩、Ｎ-オキシド、水和物、溶媒和化合物、医薬として許容される誘導体、プロドラッグ、互変異性体及び/又は異性体を提供する。 The present invention also provides the following formula II or III:

{Where,
In Formula II, one or more W and one or more Z, and in Formula III, one or more Z and C (= Q) NR are one or more of any one of the ring carbons, 3, 4, and 6-10 positions. To the ring carbon of
here,
Q, R, W, Y, and Z are as defined in Formula I;
x is an integer from 2 to 4 and
L is a linker group having a valence x}, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, pharmaceutically acceptable derivative, prodrug, Variants and / or isomers are provided.

  It is understood that each monomer subunit of the compound can be different to avoid any suspicion. However, in each subunit, each substitution is within the definition provided. In other words, compounds having two or more units of formula I and bonded together should be considered within the definition of formula II above.

  Preferably x is 2.

Preferably L is a linker group containing nitrogen, more preferably V ¹ -[(CHR) _q NR ⁴ ] _r (CHR) _q -V ^2.
{In the group,
V ¹ and V ² are each independently oxygen, NR ⁴ or CHR;
q is an integer from 0 to 5 and has a different value for each subunit of linker L;
r is an integer from 0 to 2;
R ⁴ is as defined in Formula I, or when r is greater than 0, R and R ⁴ may together form an optionally substituted branched or straight chain alkylene}. The linker group represented.

Preferably R and R ⁴ are each independently H, CH ₃ or C ₂ H ₅ , or if r is greater than 0, R and R ⁴ are preferably —CH ₂ CH ₂ CH ₂ —. It is.

Most preferably, the linker group is:
-(CH ₂ ) ₂ NH (CH ₂ ) _2-
-(CH ₂ ) ₃ -NMe- (CH ₂ ) _3-
-(CH ₂ ) ₂ NH (CH ₂ ) ₂ NH (CH ₂ ) _2-
-(CH ₂ ) ₂ NH (CH ₂ ) ₃ NH (CH ₂ ) _2-
-(CH ₂ ) ₂ NMe (CH ₂ ) ₂ NMe (CH ₂ ) _2-
-(CH ₂ ) ₂ NMe (CH ₂ ) ₃ NMe (CH ₂ ) _2-
-N, N'-bis (ethylene) piperazine-
-N, N'-bis (propylene) piperazine-,
-(CH ₂ ) _S NH (CH ₂ ) _t-
-(CH ₂ ) _S N alkyl (CH ₂ ) <sub>t-
- (CH 2) S NH (</sub> CH 2) t NH (CH 2) u -, and
-(CH ₂ ) _s N alkyl (CH ₂ ) _t N alkyl (CH ₂ ) _u-
(Where s, t and u are integers from 2 to 6)
Will be chosen from.

｛式中、
１以上のＺ及び１以上のＣＯ₂Ｈ基は、環炭素の１つ、又は３、４、及び６〜１０位のいずれかにおける複数の環炭素に結合し；かつ
Ｑ、Ｙ、及びＺは、式Ｉに定義されるとおりである｝で表される化合物を式Ｉ、II、又はIIIのアミドに変換することを含む。 According to a second aspect, the present invention provides a process for preparing a compound of formula I, II, or III. The method comprises the following formula IV:

{Where,
1 or more Z and one or more CO ₂ H groups, one of the ring carbons, or 3,4, and coupled to a plurality of ring carbon at either 6-10 position; and Q, Y, and Z The compound of formula I, as defined in formula I} is converted to an amide of formula I, II, or III.

  When the intermediate compound of formula IV is new, the present invention extends to the compound of formula IV as defined above.

｛式中、
Ｚは式Ｉに定義されるとおりである｝
で表される化合物を、ＹＮＨ₂｛式中、Ｙは式Ｉで定義されるとおりである｝と反応させる工程を含む。 According to a third aspect, the present invention provides a process for the preparation of a compound of formula IV wherein Q is O and CO ₂ H is bonded to the 4-position. The method comprises the following formula V:

{Where,
Z is as defined in Formula I}
And a step of reacting the compound represented by: YNH ₂ (wherein Y is as defined in Formula I).

  In a fourth aspect, the present invention provides a pharmaceutical or veterinary composition comprising a compound of formula I, II, or III as defined above with a pharmaceutically or veterinary acceptable carrier.

  In a fifth aspect, the present invention provides a method for treating and / or preventing a cell proliferative disorder. The method includes administering a therapeutically effective amount of a compound of formula I, II, or III to a subject in need thereof.

  The invention also provides the use of a compound of formula I, II, or III in the manufacture of a medicament for the treatment and / or prevention of a cell proliferative disorder.

  The present invention further provides a compound of formula I, II, or III for use in the treatment and / or prevention of cell proliferative disorders.

  The present invention further provides the use of a compound of formula I, II, or III as cytotoxic, anti-neoplastic, anti-tumor and / or anti-cancer agents.

Detailed Description of the Invention For the purposes of this specification, it is clear that the word "comprising" means "including but not limited to" and the word "consisting" has the corresponding meaning. Will be understood.

  As used herein, the singular forms “a”, “an”, and “the” include plural aspects unless the context clearly dictates otherwise. Thus, for example, “a compound of formula I, II, or III” includes a single compound as well as two or more compounds.

The terms “C _1-4 alkyl” or “C _1-6 alkyl” are used alone or “optionally substituted C _1-4 or C _1-6 alkyl”, “C _1-6 haloalkyl”. Or used in compound terms such as “C _1-6 aminoalkyl” to refer to a straight, branched, or cyclic hydrocarbon group having from 1 to 6 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

  The term “heterocyclic group” used alone or in compound words such as “optionally substituted saturated or unsaturated heterocyclic group” refers to a monocyclic or polycyclic heterocyclic group. And a heterocyclic group containing at least one heteroatom selected from nitrogen, sulfur and oxygen.

Suitable heterocyclic groups include N-containing heterocyclic groups such as 3-6 membered unsaturated heterocyclic monocyclic groups containing 1-4 nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl. , Pyrazinyl, pyridazinyl, triazolyl or tetrazolyl;
3-6 membered saturated heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl;
Unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, or tetrazolopyridazinyl;
A 3-6 membered unsaturated heteromonocyclic group containing an oxygen atom, for example pyranyl or furyl;
A 3- to 6-membered unsaturated heteromonocyclic group containing 1-2 sulfur atoms, for example thienyl;
A 3-6 membered unsaturated heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as oxazolyl, isoxazolyl, or oxadiazolyl;
A 3- to 6-membered saturated heterocyclic monocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl;
Unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl or benzoxdiazolyl;
A 3- to 6-membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl or thiadiazolyl;
3 to 6-membered saturated heterocyclic monocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl; and 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms Includes unsaturated fused heterocyclic groups such as benzothiazolyl or benzothiadiazolyl.

  The term “optionally substituted” is alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, Haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, Alkenyl acyl, alkynyl acyl, aryl acyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, arylsulfur Selected from nyloxy, heterocyclyl, heterocycloxy, heterocycloamino, haloheterocyclyl, alkylsulfenyl, arylsulfenyl, carboalkoxy, carboaryloxy, mercapto, alkylthio, benzylthio, acylthio, phosphorus-containing groups, etc. It refers to a group that can be further substituted or unsubstituted with one or more groups. In certain instances in the specification, preferred substituents have been described where substituents may be present.

  The term “carbocycle” refers to fully saturated, partially unsaturated, or aromatic carbocyclic radicals having from 3 to 12 carbon atoms in a single ring or multiple condensed rings, such as cycloalkyl, cycloalkenyl, and aryl. Point to. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, indane, and biphenyl.

  The term “halo” or “halogen” refers to fluorine, chlorine, bromine, or iodine. When halogen substitution is present, the preferred halogen is chlorine or bromine.

Alone, or, for example, "C _1-6 haloalkoxy" or "C _1-6 aminoalkoxy", "C _1-6 alkoxy" as used compound words such as the alkyl moiety of 1 to about 6 carbon atoms It refers to a straight-chain or branched oxy-containing radical each having. Examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy.

The term “linker group” is used herein in its broadest sense to refer to any organic group that is bonded together with adjacent units of a compound, either symmetric or asymmetric. It is possible. The linker group is preferably a nitrogen-containing linker group, whereas the linker group may instead be dispersed with O; S; optionally one or more optionally substituted aryl groups or optionally substituted heterocyclic groups, and And / or an optionally substituted C _1-20 alkylene, alkenylene, or alkynylene chain that can be dispersed with one or more O, S, or N atoms; or an optionally substituted saturated or unsaturated aryl or heterocyclic group It will be recognized that it can.

  The terms “alkylene”, “alkenylene”, and “alkynylene” are the divalent radical equivalents of the terms “alkyl”, “alkenyl”, and “alkynyl”, respectively. The two bonds linking alkylene, alkenylene, or alkynylene to adjacent groups can be from the same carbon atom in the divalent radical or from different carbon atoms.

  The linker may alternatively be of the type disclosed in International Patent Application No. WO 96/25400 by The DuPont Merck Pharmaceutical Company. All of the disclosures are incorporated herein by cross-reference.

The term “alkenyl” refers to a straight or molecular chain radical having at least a carbon-carbon double bond of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms. More preferably, the alkenyl radical is “C _2-6 alkenyl”. Examples of alkenyl include ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl.

The term “alkynyl” refers to a straight or branched chain radical having 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms. More preferably, the alkynyl radical is “C _2-6 alkynyl”. Examples of alkynyl include propargyl and butynyl.

  The conversion step in the process for the preparation of a compound of formula I, II or III comprises an intermediate step, in which the compound of formula IV can be converted to imidazolide and then reacted with a suitable amine. To obtain the target amide of formula I, II, or III. Alternatively, the reaction involves acid halide conversion of a carboxylic acid of formula IV followed by reaction with an amine to give a target amide of formula I, II, or III. The reagent in the second route is preferably thionyl chloride. It will be clearly understood in the above description that in the case of bis compounds, the two units of the carboxylic acid react with a suitable diamine to form a diamide.

  It will be appreciated that salts of the compounds of formula I, II, or III are preferably pharmaceutically acceptable, but salts that are not pharmaceutically acceptable are within the scope of the present invention. This is because the salt is useful as an intermediate in the production of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium, and alkylammonium; pharmaceutically acceptable inorganic acids such as hydrochloric acid, Including acid addition salts such as orthophosphoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid; pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, Maleic acid, hydroxymaleic acid, fumaric acid, citric acid, lactic acid, mucoic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, trihalomethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid , Sulfanilic acid, aspartic acid, glutamic acid, Salts such as detoic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid are included.

  In addition, some of the compounds of the present invention may form solvates with water or conventional organic solvents. Such solvates are included within the scope of the present invention.

  The term “pharmaceutically acceptable derivatives” is not intended to be pharmaceutically acceptable salts, hydrates, esters, amides, active metabolites, analogs, residues, or biologically or otherwise undesirable. Means other compounds that induce the desired pharmacological and / or physiological effects.

  The term “prodrug” is used herein in its broadest sense to include a compound that is converted in vivo to a compound of formula I, II, or III.

  The term “tautomer” is used herein in its broadest sense and includes a compound of formula I, II, or III that can exist in equilibrium between two isomeric forms. .

  The term “isomer” is used herein in its broadest sense and includes structural, geometric, and stereoisomers. When a compound of formula I, II, or III has one or more asymmetric centers, the compound can exist in an enantiomeric form.

  The composition of the invention comprises at least one compound of formula I, II, or III, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic agents. Each carrier, diluent, adjuvant, and / or excipient must be pharmaceutically “acceptable” in the sense of being compatible with the other ingredients of the composition and innocuous to the subject. Compositions include those suitable for oral, rectal, nasal, topical (buccal and sublingual), vaginal, or parenteral (subcutaneous, intramuscular, intravenous and intradermal) administration. The composition exists in unit dosage form and can be prepared by methods well known in the pharmaceutical art. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions allow the active ingredient to be uniformly and intimately associated with the liquid carrier, diluent, adjuvant and / or excipient or finely divided solid carrier, or both, and then required If there is, it is prepared by shaping the product.

  The term “cell proliferative disorder” means that a cell or cells exhibit abnormal growth, typical abnormal growth, leading to a neoplasm, tumor or cancer.

  Cell proliferative diseases include, for example, breast, lung, prostate, kidney, skin, nerve, ovary, uterus, liver, pancreas, epithelium, stomach, intestine, exocrine line, endocrine gland, lymph, hematopoietic system, or head and neck tissue Including cancer.

  In general, neoplastic diseases are diseases in which the abnormal growth of cells results in a mass of tissue called a neoplasm or tumor. Neoplasms have varying degrees of abnormality in terms of structure and behavior. Some neoplasms are benign, while other neoplasms are malignant or cancerous. Effective treatment of neoplastic diseases can be considered a valuable contribution to the search for cancer prevention or treatment methods. The compounds of the present invention are preferably used in the treatment of leukemia, lymphoma, multiple myeloma, sarcoma, and brain tumors, and in the treatment of lung, breast, ovarian, testis, and colon cancer.

  The term “subject” as used herein refers to any animal having a disease or condition that requires treatment with a pharmaceutically active agent. The subject can be a mammal, preferably a human, or can be a non-human primate, or a non-primate used, for example, in animal model studies. While it is particularly contemplated that the compounds of the present invention are suitable for use in human pharmaceutical therapy, the compounds may be used in pet animals such as dogs and cats, as well as horses, ponies, donkeys, mules, llamas, alpaca, pigs, cattle And veterinary treatments including treating domestic animals such as sheep, or zoo animals such as primates, felines, canines, bovines, and ungulates.

  Suitable mammals include members of primates, rodents, rabbits, whales, carnivores, terridae, and artiodactyla. The members of the ostium and artiodactyl are particularly preferred due to the similarity and economic importance of the organism.

  For example, the artiodactyles are divided into nine families: pigs (Boars), peccaries (Peccaries), hippopotamus (Chipaceae), camels (Camelids), sika deer (Lepidoptera), giraffes and okapis (Giraffidae), deer Includes approximately 150 species of livestock that are divided into (Deeridae), Pronghorn (Pronghornaceae), and cattle, sheep, goats, and antelopes (Bovineae). Many of these animals are used as food animals in various countries. More importantly, many economically important animals, such as goats, sheep, cattle, and pigs, have biological similarity and high genomic homology.

  The terrestrial hoof includes horses and donkeys, both of which are economically important and closely related. It is well known that horses and donkeys can in fact be mated.

  As used herein, the term “therapeutically effective amount” means an amount of a compound of the invention effective to obtain a desired therapeutic response, eg, to prevent or treat a cell proliferative disorder. .

  A specific “therapeutically effective amount” refers to the particular disease being treated, the physical condition of the subject, the type of subject being treated, the duration of treatment, the nature of the combination treatment (if any), and the particular formulation used and It will clearly vary with factors such as the structure of the compound or its derivatives.

  The compounds of the present invention may be further mixed with other drugs to provide a potent combination. It is intended to include any chemically compatible combination of pharmaceutically active agents so long as the combination does not exclude the activity of the compound of formula I, II, or III. It will be appreciated that the compounds of the invention and other drugs may be administered in divided, sequential or simultaneous fashion.

  Other drugs include, for example, mitotic inhibitors such as taxol, antimetabolites such as 5-fluorouracil, antihormonal modulators such as tamoxifen, DNA-reactive agents such as cisplatin, or interleukin-2 (IL-2 ) Or one or more other anti-tumor agents including biological agents such as antibodies.

  In order to reduce toxic side effects or side effects on a person who receives either or both of a compound of formula I, II, or III or other anticancer agent, the second DNA binding anticancer therapeutic agent is of formula I, II, or III. Can be used in combination with the administration of the compounds.

  The term “toxic side effects” or “side effects” refers to the harmful and undesired effects of chemotherapy in the subject's normal, non-pathological tissues and organs. For example, toxic side effects can include myelosuppression (including neutropenia), cardiotoxicity, hair loss, gastrointestinal toxicity (including nausea and vomiting), neurotoxicity, lung toxicity, and asthma. The aldehyde releasing compound and / or chemotherapeutic agent can be administered orally, topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and solvents.

  It is contemplated that the compounds of the present invention can be administered in the form of a prodrug that is activated in the tumor. In such a form, the activating agent binds to the trigger domain and such compounds can be designed to be activated, for example, by local hypoxia within the tumor population. Suitable methods are well known in the art. See, for example, Denny, 1996; McFadyen et al, 1996.

  The compounds of the present invention can be used in combination with drugs that reduce the side effects caused by drug treatment, such as granulocyte colony stimulating factor, or antiemetics.

  A “pharmaceutically acceptable carrier” as used herein is a pharmaceutically acceptable solvent, suspending agent, or solvent for delivering a compound of formula I, II, or III to a subject. . The carrier can be a liquid or a solid and is chosen in the planned manner of administration. Each carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and be innocuous to the subject.

  The compounds of Formula I, II, or III can be administered orally, topically, or parenterally in unit dosage formulations containing conventional non-toxic pharmaceutically acceptable monomers, adjuvants, and solvents. The term parenteral as used herein includes subcutaneous injections, aerosols for administration to the lung or nasal cavity, intravenous, intramuscular, intrathecal, injection or infusion techniques.

  The present invention provides suitable topical, oral, and parenteral pharmaceutical formulations for use in the novel therapeutic methods of the present invention. The compounds of the invention can be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. Compositions for oral use can include one or more agents selected from the group of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically refined and palatable formulation. Suitable sweeteners include sucrose, lactose, glucose, aspartame, or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinyl pyrrolidone, xanthan gum, bentonite, alginic acid, or agar. Suitable flavoring agents include peppermint oil, winter green, cherry, orange, raspberry balm. Suitable preservatives include sodium benzoate, vitamin E, alpha tocopherol, ascorbic acid, methyl paraben, propyl paraben, or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate. Tablets are non-toxic pharmaceutically acceptable excipients that contain the active ingredient in admixture with excipients suitable for the manufacture of tablets.

  Excipients include, for example, (1) inert diluents such as calcium carboxylate, lactose, calcium phosphate, or sodium phosphate; (2) granules and disintegrants such as corn starch or alginic acid; (3) binders such as starch Gelatin, or acacia; and (4) lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or coated by well known techniques to delay disintegration and absorption in the intestinal tract and, as a result, provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coating is performed using the techniques described in US Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, thereby forming osmotic therapeutic tablets for controlled release.

  The compounds of formula I, II or III as well as the pharmaceutically active agents useful in the methods of the invention are performed individually or together by injection or in portions over a period of time for in vivo applications. It can be administered parenterally by perfusion. Administration can be intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, intracavity, transdermal, for example infusion with an osmotic pump. For in vitro studies, the agent can be added or dissolved in a suitable biologically acceptable buffer and added to the cell or tissue.

  Parenteral preparations include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, aqueous alcoholic solutions, emulsions or suspensions, including saline and buffered cultures. Parenteral solvents include sodium chloride solution, Ringer's dextrose solution, dextrose and sodium chloride solution, lactated Ringer's intravenous solvent, body fluids and nutritional supplements (e.g., based on Ringer's dextrose solution), electrolyte supplements, etc. Can also be included. Preservatives and other additives such as antibacterial agents, antioxidants, chelating agents, growth factors and inert gases may be present.

  In general, “treat”, “treatment” and the like are used herein to mean acting on a subject, tissue or cell to obtain a desired pharmaceutical and / or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the symptoms of the disease or its symptoms and / or may be therapeutic in terms of partially or completely treating the disease. . As used herein, “treat” encompasses treating or preventing a disease in vertebrates, mammals, and particularly humans, and (a) is susceptible to, but diagnosed as having a disease. Preventing the onset of the disease in an untreated subject; (b) inhibiting the disease, ie stopping the development of the disease; (c) relieving or ameliorating the effect of the disease, ie Including causing regression of the disease effect.

  The present invention includes various pharmaceutical compositions useful for ameliorating disease. A pharmaceutical composition according to one embodiment of the present invention comprises a compound of formula I, II or III, an analog, a derivative or salt thereof, or a compound of formula I, II or III and one or more pharmaceutically active agents. And the combination is made into a form suitable for administration to a subject using carriers, excipients, and additives or adjuvants. Frequently used simple substances or adjuvants are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and their derivatives, animal and vegetable oils, polyethylene glycols And solvents such as sterilized water, alcohol, glycerol, and polyhydric alcohols. Intravenous vehicles include body fluids and nutrient supplements. Preservatives include antibacterial agents, antioxidants, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include non-toxic excipients including aqueous solutions, salts, preservatives, buffers, etc., such as Remington's Pharmaceutical Sciences, 20th ed., Williams and Wilkins, Pennsylvania, USA and The National Formulary. XIV., 14th ed. Washington: American Pharmaceutical Association (1975). This content is incorporated herein. The pH and the exact concentration of the various components of the pharmaceutical composition are adjusted according to routine techniques in the art. See Goodman and Gilman, The Pharmacological Basis for Therapeutics (7th ed., 1985).

  The pharmaceutical composition is preferably prepared and administered in dosage units. Solid dosage units can be tablets, capsules, and suppositories. Depending on the activity of the compound, the mode of administration, the nature and severity of the disease, the age and weight of the subject, different daily doses may be used for treating the subject. Under certain conditions, high or low daily dosages may be appropriate. Daily dosage administration is by single administration in the form of individual dosage units or in the form of several smaller dosage units and by multiple administrations of divided doses over a specific period of time. Can be done.

  The pharmaceutical composition according to the invention is administered locally or systemically in a therapeutically effective dose. Effective amounts for this use will, of course, depend on the severity of the disease and the weight and general condition of the subject. Typically, the dosage used in vitro will provide useful guidance on the amount useful for in situ administration of the pharmaceutical composition. The animal model can then be used to determine an effective dose for treating cytotoxic side effects. Various ideas are described, for example, in Langer, Science, 249: 1527, (1990). Oral use formulations may be in the form of hard gelatin capsules. In the capsule, the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. The formulation may be in the form of a soft gelatin capsule. In the capsule, the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

  Aqueous suspensions usually contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; (2) a dispersant or wetting agent. (A) natural phosphatides such as lecithin; (b) condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate; (c) condensation products of ethylene oxide and long chain fatty alcohols, such as heptadeca Ethyleneoxyethanol; (d) condensation products of ethylene oxide with fatty acid-derived partial esters and hexitol, such as polyoxyethylene sorbitol monooleate (e) ethylene oxide with fatty acid-derived partial esters and hexitol anhydride Condensed products It can be a drug such as monooleate polyoxyethylene sorbitan.

  The pharmaceutical compositions may be in the form of a sterile injectable or oily suspension. The suspension may be formulated according to well known methods using suitable dispensing or wetting agents and the above suspensions. A sterile injectable preparation is a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Of the acceptable solvents and solvents that can be used, water, Ringer's solution, and isotonic sodium chloride solution are preferred. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any brand of fixed oil is used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

  Compounds of formula I, II, or III can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

A compound of formula I, II, or III may be present for use in the form of a veterinary composition. The composition can be prepared, for example, by methods conventional in the art. Examples of such veterinary compositions are
(a) Oral administration, external application, eg liquid medicine (eg aqueous or non-aqueous solution or suspension); tablets or pills; powder, granules or pellets mixed with sample; paste applied to tongue, etc. ;
(b) parenteral administration, eg, by subcutaneous injection, intramuscular injection, or intravenous injection of a sterile solution or suspension; or (where appropriate) the suspension or solution is intramammary through the nipple Administration by intramammary injection introduced into
(c) topical application, such as cream, ointment or spray applied to the skin;
(d) includes compositions applied to vaginal applications such as vaginal suppositories, creams or foams.

  The term “therapeutically effective amount” means an amount of a compound of formula I, II, or III of the present invention effective to obtain the desired therapeutic response. “Prophylactically effective amount” has a similar definition.

  The dosage level of a compound of formula I, II, or III of the present invention is on the order of about 0.5 mg to about 20 mg / kg body weight. A preferred dosage range is from about 0.5 mg to about 10 mg / kg body weight per day (about 0.5 gms to about 3 gms per patient per day). The amount of active ingredient mixed with a carrier material that provides a single dosage will vary depending upon the host treated and the particular mode of administration. For example, formulations intended for oral administration to humans may contain about 5 mg to 1 g of active compound with a suitable and convenient amount of carrier material. The amount of the carrier material can vary from 5 to 95% of the total composition. Dosage unit forms will generally contain about 5 mg to 500 mg of the active ingredient.

  Optionally, the compounds of the invention are administered in a divided dosage regime, so that there are a total of at least 2 doses in the dosage regime as a whole. Administration is preferably given at least every 2 to 4 hours or longer. For example, the compound can be given every hour or every 30 minutes. In certain preferred embodiments, the divided dosing schedule is an interval from the first dose and is sufficiently long so that the level of active compound in the blood is about 5 to 5 of the maximum plasma level achieved after the first dose. After an interval of reduction to 30%, a second dose of the compound of the invention is included, thereby maintaining an effective amount of active agent in the blood. Optionally, one or more subsequent doses may be given at corresponding intervals from each previous dose, preferably when the plasma level is reduced to about 10-50% of the previous early maximum. .

  However, the particular dosage level for a particular patient is subject to the activity, age, weight, general health, sex, diet, time of administration, route of administration, exclusion rate, drug combination, and treatment of the particular compound used. It will depend on a variety of factors, including the severity of the particular disease you are having.

  The invention will be described with reference to the following examples. These examples should not be construed as limiting the invention in any way.

The structures of representative compounds of the present invention are summarized in Table 1. It will be clear that forms A and B represent general formulas I and II, respectively.

footnote
^a R = (CH ₂ ) ₂ NMe ₂ . However, 20bb [(S) -CH (Me) CONMe ₂ ] and 20 cc [(S) -CH (Me) CH ₂ NMe ₂ ] are excluded.

The homophthalic acid analogs 16a-d are prepared by applying the chemical pyridine example method (Ames and Dodds, 1972). Analog 16e is prepared by using another literature method (Kubo et al, 1986). 16 was reacted with Vilsmeier reagent to give compound 17 (Scheme 2a) (Deady and Rodemann, 2001). Compound 18d was previously formed by refluxing 17b with phosphorus oxychloride for 48 hours (Deady and Rodemann, 2001). However, the same conversion was carried out in an experimentally preferred procedure by reacting with methylamine in tetrahydrofuran / dimethylformamide at room temperature; another 17 reacted similarly. It is known to react isocoumarin with ammonia to give isoquinolone [the Gabriel reaction (Gabriel, 1885)], which reacts with alkyl (Jhalani et al, 1989) and aryl (Modi and Usgaonkar, 1979) amines. Expanded to related systems. Compound 17 reacts with a wide selection of amines under very mild conditions to give 18 in general good yield (Scheme 2b). On the other hand, reacting 17b with N, N′-bis- (2-aminoethyl) -N, N′-dimethylpropane-1,3-diamine gave an example of bis compound 18aa .

Since a slight change occurred when ammonia was used as the alkylamine and the product separated from the reaction mixture was the ammonium salt of the acid; liberation of 18c required treatment with acid.

Reacting 17 with an arylamine fails in the absence of triethylamine and appears to require moderate base catalysis. Alkylamines act as nucleophiles and bases, while arylamines require the presence of stronger basic, nucleophilic triethylamines. Nevertheless, while the reaction competes with the arylamine, dimethylamine is liberated, creating a complex situation and leading to the formation of by-products. By-product formation was minimized by using excess arylamine. In the case of 3,4-dimethoxyaniline, this complex situation does not occur. This is because the starting product 19 was quite insoluble. In order to obtain a complete reaction, it was required to reflux a mixture of 19 , many 3,4-dimethoxyaniline and triethylamine in pyridine for 8 hours and gave 18q in 78% yield ( Scheme 2c).

Carboxamide in Table 1, the intermediate acid chloride (is derived from 18 with thionyl chloride were reacted, not isolated) or imidazolide (18 a is not a 1,1'-carbonyldiimidazole, from reaction, (Not isolated) was prepared by reacting with the appropriate amine.

Experimental NMR spectra, on Bruker AM-300 spectrometer were recorded operating at 300.13 MHz ⁽¹ H) and 75.47MHz ⁽¹³ C), and on Bruker DRX-400 spectrometer, 400.13 MHz ( ¹ H) and 100.62 MHz ( ¹³ C). The chemical shift was then recorded as the σ value (ppm) for Me ₄ Si. COSY spectra were recorded on the AM-300 spectrometer using the Bruker Library pulse program COZY.AUR. HMQC and HMBC spectra were recorded on a DRX-400 spectrometer using the pulse programs INV4GSTP and INV4GSLPLRND, respectively. NOESY spectra were recorded on a Bruker DRX-400 spectrometer using the pulse program NOESYTP from Bruker Libray. Various standard techniques were used to identify proton-bonded carbon in the ¹³ C NMR spectrum. Mass thermal spray mass spectrometry spectra (ESMS) were measured on a VG Bio-Q triple quadrupole mass spectrometer using acetonitrile or methanol with formic acid (1%) as the moving bed. EI and LSI (3-nitrobenzyl alcohol in liquid matrix) mode high resolution mass spectrometry was obtained from Dr N. Davies, University of Tasmania, Australia. Microanalysis was performed at the Campbell Microanalytical Laboratory, University of Otago, New Zealand.

  N, N′-bis- (2-aminoethyl) -N, N′-dimethylpropane-1,3-diamine was utilized (Deady et al, 2000), and other amines were commercial samples.

Precursor compounds 16a-d were prepared by applying the method for pyridine analogs (Ames and DoDdds, 1972).

Ethyl (3-carboxyquinolin-2-yl) acetate (16a)

Ethyl (3-carboxy-8-methylquinolin-2-yl) acetate (16b)
(Deady and Rodemann, 2001).

Ethyl (3-carboxy-7-methoxyquinolin-2-yl) acetate (16c)
Obtained (from ethanol) as an orange solid, mp 193-195 ° C. (dec). Occasionally the compound was obtained as a red oil. The oil is triturated with cold acetonitrile and solidified. No recrystallization is required before use in the next step.

Ethyl (3-carboxyquinoxalin-2-yl) acetate (16d)
Obtained as a brown semi-fluid material. The material was used in the next step in this state.

Ethyl (3-ethoxycarbonyl [1,8] naphthyridin-2-yl) acetate (16e)
Obtained from 2-aminonicotinaldehyde and diethyl 1,3-acetone dicarboxylate as an orange solid, mp 79-80 ° C. (from ethyl acetate) by the method reported for the dimethyl analog (Kubo et al, 1986).

Example 1: Preparation of 4-dimethylaminomethylene-6-methyl-4H-pyrano [4,3-b] quinoline-1,3-dione (17b).
2 is an example of a general preparation of diones of formula V.
Phosphorous oxychloride (13 mL) was added to dimethylformamide (40 mL) with stirring at 0 ° C. After 20 minutes, a solution of ethyl (3-carboxy-8-methylquinolin-2-yl) acetate 16b (10.0 g) in dimethylformamide (10 mL) was added in one portion and the mixture was stirred at room temperature for another 2 hours. Stir. The precipitate was collected by filtration and washed with cold acetone to give the product as an orange solid (10.0 g, 97%), mp> 295 ° C. (decomposition-forming needles> 280 ° C.).

The following compounds were prepared using similar methods.
4-Dimethylaminomethylene-4H-pyrano [4,3-b] quinoline-1,3-dione (17a)

4-Dimethylaminomethylene-7-methoxy-4H-pyrano [4,3-b] quinoline e-1,3-dione (17c)

4-Dimethylaminomethylene-4H-pyrano [3,4-b] quinoxaline-1,3-dione (17d)
Prepared from crude 16d in modified ratio, 1 g · 16d : 0.8 ml: 0.8 mL · POCl ₃ : 1.6 mL · DMF. The reaction mixture was dehumidified and heated at 75 ° C. for 16 hours, then cooled, diluted with cold dichloromethane and placed at −18 ° C. for 1 hour. The red brick colored solid was filtered and washed thoroughly with cold dichloromethane with stirring to give dione (22%), mp 133-139 ° C. (from 3-chloroquinoxaline-2-carboxylic acid).

9-dimethylaminomethylene-9H-pyrano [4,3-b] [1,8] naphthyridine-6,8-dione (17e)
Prepared from diester 16e in a modified ratio, 1 g · 16e : 0.8 mL · POCl ₃ : 1.6 mL · DMF. The reaction mixture was heated at 75 ° C. for 16 hours while dehumidifying. It was then cooled, diluted with cold dichloromethane and placed on ice for 1 hour. The orange solid was filtered and washed thoroughly with cold dichloromethane with thorough stirring. The orange dione mass showed a yield of over 100%. The material was used in this state in further reactions within 24 hours. This is because the substance is decomposed by standing for a long time.

Example 2: Preparation of 2,6-dimethyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18d) Reacting with excess amine according to scheme 2b Is an example of generally preparing a carboxylic acid of formula IV from a precursor compound of formula V.
A solution of methylamine in tetrahydrofuran (7.0 ml, 2M) was added to 17b (0.8 g) in dimethylformamide (20 ml) and the whole was stirred at room temperature for 16 hours. The solid was collected by filtration and washed with cold acetone to give a pale yellow solid (0.60 g, 79%), mp> 300 ° C. (forming cubics> 290 ° C.).

The following compounds were made using similar procedures.
2-Methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18b)
Prepared from 17a and methylamine in a similar manner as 18d to give a yellow solid (69%), mp> 305 ° C. (formed needles> 230 ° C.).

2-Butyl-6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18f)
From 17b and butylamine were prepared similarly to 18 d, a bright yellow solid (82%) was obtained as mp259 ℃.

２-[(２-ジメチルアミノ)エチル]-１-オキソ-１,２-ジヒドロベンゾ[ｂ][１,６]ナフチリジン-４-カルボン酸 (１８ｌ)
１７ａ及びＮ,Ｎ-ジメチルエチレンジアミンから、１８ｄと同様に調製し、黄色固体(５２％)、ｍｐ２３２-２３３℃として得た。

2-[(2-Dimethylamino) ethyl] -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18k)
17b and N, N- dimethylethylenediamine, were prepared similarly to 18 d, a yellow solid (78%) was obtained as mp254-255 ℃.

2-[(2-Dimethylamino) ethyl] -1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (181)
17a and N, N- dimethylethylenediamine, were prepared similarly to 18 d, a yellow solid (52%) was obtained as mp232-233 ℃.

(S) -6-Methyl-1-oxo-2- (1-phenylethyl) -1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18m)
Prepared analogously to 18d from 17b and (S)-(−)-α-methylbenzylamine. However, the product remained in the dimethylformamide solution. Water was added to the reaction mixture and the resulting precipitate was collected by filtration and washed with water to give the product as a yellow solid (79%), mp 234-235 ° C.

7-methoxy-2-methyl-1-oxo-1,2-dihydro-benzo [b] [1,6] naphthyridine-4-carboxylic acid (18w)
Prepared similarly from 18c from 17c and methylamine and obtained as a yellow solid (86%) (from dimethyl sulfoxide / 1,4-dioxane), mp> 300 ° C.

7-Methyl-6-oxo-6,7-dihydropyrido [2,3-b] [1,6] naphthyridine-9-carboxylic acid (18y)
Prepared similarly from 18e from 17e and methylamine. However, after the reaction, volatile substances were removed under reduced pressure and water was added. The resulting suspension was stirred and basified with 10% sodium hydroxide. It was then acidified (by dropwise addition) with concentrated hydrochloric acid and the brown solid was filtered to give 18y (from dimethyl sulfoxide / 1,4-dioxane), mp 300 ° C.

2-Methyl-1-oxo-1,2-dihydropyrido [3,4-b] quinoxaline-4-carboxylic acid (18z)
Prepared similarly from 18d from 17d and methylamine. However, after the reaction, volatile substances were removed under reduced pressure to obtain 18z methylamine salt as a yellow-brown solid. The material was suspended in a small amount of water and 10% sodium hydroxide was added dropwise with stirring until a solution was obtained. The solution is acidified with a minimum amount of concentrated hydrochloric acid and the separated solid is filtered and washed with water to give the free acid as a yellow solid (52%), mp> 300 ° C. (dimethyl sulfoxide / 1,4- From dioxane).

５％の塩酸(２０ｍｌ)中のアンモニウム塩(０.１５ｇ)を、還流下で、透明な溶液が得られるまで(１０分)熱した。冷却後、１０％水酸化ナトリウムでｐＨ４に調節した。沈殿をろ過で収集して黄色固体(０.１３ｇ、９３％)、ｍｐ＞３００℃(針状晶の形成後＞２５５℃)として酸を得た。

6-Methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18c)
A mixture of 17b (1.0 g) in dimethylformamide (25 ml) was stirred at room temperature under a stream of ammonia for 4 hours. The precipitate that formed after dissolution of the starting material was collected by filtration and washed thoroughly with acetone to give a yellow solid (0.70 g, 78%), mp> 300 ° C. (> 255 ° C. after formation of needles). ) As the product ammonium salt.

Ammonium salt (0.15 g) in 5% hydrochloric acid (20 ml) was heated under reflux until a clear solution was obtained (10 min). After cooling, the pH was adjusted to 4 with 10% sodium hydroxide. The precipitate was collected by filtration to give the acid as a yellow solid (0.13 g, 93%), mp> 300 ° C. (> 255 ° C. after formation of needles).

Example 3: 6-Methyl-1-oxo-2- (2,2,2-trifluoroethyl) -1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18 g) An example of the general preparation of a carboxylic acid of formula IV from a precursor compound of formula V by reacting with an amine in the presence of an excess of triethylamine according to Preparation Scheme 2b.
To a stirring suspension of dione 17b (1.00 g, 3.54 mmol) in N, N-dimethylformamide (15 ml) was added triethylamine (2.5 ml) with stirring. 2,2,2-trifluoroethylamine (0.40 g, 4.04 mmol) was added and the whole was stirred at room temperature for 16 hours. The solid was filtered and washed with water to give yellow acid (64%), mp 297-300 ° C. (needle crystals formed at 234-235 ° C.).

The following compounds were made using similar procedures.
2-Ethyl-6-methyl-1-oxo-1,2-dihydro-benzo [b] [1,6] naphthyridine-4-carboxylic acid (18e)
From 17b and ethylamine was prepared similarly to 18d. However, the initial addition of ethylamine was made at 0 ° C. and a positive pressure of nitrogen was maintained throughout the operation and was obtained as a yellow solid (72%), mp 251-253 ° C.

2- (2-Hydroxyethyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18h)
Prepared from 17b and ethanolamine analogously to 18g and obtained as a yellow solid (64%), mp 258-261 ° C.

2- (Ethoxycarbonylmethyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18i)
Prepared in the same manner as 18g from 17b , triethylamine, and glycine ethyl ester hydrochloride. However, water is added to the reaction mixture before filtering the acid. The product was obtained as a yellow solid (65%), mp 277-280 ° C.

2- (3-Ethoxycarbonylpropyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18j)
Prepared analogously from 18b from 17b and ethyl 4-aminobutyrate hydrochloride. However, 1,4-dioxane was used as a solvent. After 16 hours, water was added to the reaction mixture and the yellow solid was filtered and washed with a small amount of 3% hydrochloric acid and then with water to give acid 18j (59%), mp 186-188 ° C. Gave. The material is used in the next step without further purification, but can be recrystallized from toluene as a yellow solid.

2- (3,4-Dimethoxybenzyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18r)
Prepared from 17b and veratylamine analogously to 18g and obtained as a yellow solid (77%), mp 256-257 ° C.

2- [2- (3,4-Dimethoxyphenyl) ethyl] -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18s)
From 17b and 3,4-dimethoxy-phenethylamine was prepared as 18 g, and a yellow solid (79%) was obtained as mp280-282 ℃.

6-Methyl-1-oxo-2- (pyridin-2-yl) methyl-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18t)
Prepared similarly from 18b from 17b and 2-aminomethylpyridine and obtained as a yellow solid (57%), mp> 300 ° C.

6-Methyl-1-oxo-2- [3- (2-oxopyrrolidin-1-yl) propyl] -1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18u)
From 17b and N- (3- aminopropyl) -2-pyrrolidinone, prepared in analogy to 18 g, and a yellow solid (0.43 g, 64%), it was obtained as mp226-228 ℃.

2- [2- (1H-Indol-3-yl) ethyl] -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18v)
Prepared from 17b and tryptamine analogously to 18g and obtained as a yellow solid (91%), mp> 300 ° C.

ろ過を行ない、減圧下で乾燥させて、水を加え、そして得られた黄色固体をろ過しそして水で洗浄して、Ｎ,Ｎ-ジメチル-２-[２-(フェニルアミノ)ビニル]-８-メチルキノリン-３-カルボキサミド(３２％)、ｍｐ１４３-１４６℃ を(軽油から(ｂｐ９０-１１０℃))得た。

6-Methyl-1-oxo-2-phenyl-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18n)
Prepared similarly from 18b from 17b and aniline (10 mol equivalent). However, when filtered, the product was thoroughly washed with acetone. The acid was a lemon colored solid (41%), mp> 310 ° C. The material was used in the next step without further purification, but can be recrystallized from 1,4-dioxane.

Filter, dry under reduced pressure, add water, and filter the resulting yellow solid and wash with water to give N, N-dimethyl-2- [2- (phenylamino) vinyl] -8. -Methylquinoline -3-carboxamide (32%), mp 143-146 ° C. (from light oil (bp 90-110 ° C.)) was obtained.

6-Methyl-1-oxo-2- (4-fluorophenyl) -1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18o)
Prepared analogously to 18n from 17b and 4-fluoroaniline (10 mol equivalent). The first filtered product was the triethylamine salt of the target acid. The material was dissolved with hot 5% sodium hydroxide, filtered, and the filtrate was cooled and acidified with concentrated hydrochloric acid to give the acid as a yellow solid (26%).

Water was added to the first filtrate to obtain a yellow-green solid, which was recrystallized twice from methanol to give N, N-dimethyl 2- [2-((4-fluorophenyl) amino) Vinyl] -8-methylquinoline-3-carboxamide , mp 172-173 ° C. (100 ° C. after conversion).

反応混合液(ＤＭＦ、トリエチルアミン、及びトルエンを含む)からのろ液を、減圧下で乾燥させ、そして残渣をトルエンから再結晶化させて、開始アニリンを黄色固体(４５％収量)として得た。 6-Methyl-1-oxo-2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] -1,2-dihydrobenzo [b] [1,6] Naphthyridine-4-carboxylic acid (18p)
From 17b and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline was prepared as 18 g. The solution slowly formed and after 16 hours the volume was reduced to about 1/3 under reduced pressure and the whole was cooled on ice. The separated solid was filtered off, washed with cold toluene and recrystallized from toluene to give a yellow solid (20%), mp> 300 ° C.

The filtrate from the reaction mixture (containing DMF, triethylamine, and toluene) was dried under reduced pressure and the residue was recrystallized from toluene to give the starting aniline as a yellow solid (45% yield).

2- (3,4-Dimethoxyphenyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxylic acid (18q)
4-aminoveratrole (0.12 g), 17b (0.20 g), dimethylformamide (5 ml), and triethylamine (1 ml) were stirred at room temperature for 16 hours. The solid is present all the time and is collected by filtration and washed with a small amount of cold dichloromethane to give 4-[(3,4-dimethoxyphenyl) aminomethylene] -6-methyl-4H-pyrano. [4,3-b] quinoline-1,3-dione (19 ) was obtained as a yellow solid (0.25 g, 90%), mp 280-281 ° C.

19 (0.23 g), 4-aminoberelatrol (0.46 g), pyridine (15 ml), and triethylamine (1 ml) were heated under reflux for 8 hours (dissolution occurred during heating). The reaction mixture was left at −10 ° C. overnight and the resulting precipitate was collected by filtration and washed with a small amount of cold acetone to give the product as a yellow solid (0.18 g, 78%), mp 297 − Obtained as 298 ° C. (> 285 ° C. after needle crystal formation).

Example 4 2,2 ′-[1,3-propanediylbis [(methylimino) -2,1-ethanediyl]] bis [6-methyl-1-oxo-1,2-dihydrobenzo [b] [1, 6] Preparation of naphthyridine-4-carboxylic acid] (18aa) This is an example of the preparation of a biscarboxylic acid precursor for a compound of formula II.
N, N′-Bis- (2-aminoethyl) -N, N′-dimethylpropane-1,3-diamine (0.10 g) was added to 17b in dimethylformamide (7.5 ml) and triethylamine (0.4 ml). (0.30 g) was added to the suspension and the resulting solution was stirred at room temperature for 16 hours. The precipitate formed during the reaction was collected by filtration and stirred in ethyl acetate (10 ml) for 5 minutes. The solid was collected by filtration to give the product as a yellow solid (0.15 g, 43%), mp 224-228 ° C.

Example 5 Preparation of N- [2- (dimethylamino) ethyl] -2,6-dimethyl 1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20d) Scheme 2d Is an example of a general method of amide formation according to
Acid 18d (0.40 g) was heated in thionyl chloride (20 ml) under reflux for 30 minutes. Excess thionyl chloride was removed under reduced pressure and a solution of N, N-dimethylethylenediamine (0.5 mL) in dichloromethane (20 ml) was added to the residue. The resulting solution was stirred at room temperature for 16 hours and the solution was washed with 10% sodium chloride and water (x2). The solvent was removed under reduced pressure to give the product (from acetonitrile) as a yellow solid (0.48 g, 95%), mp 167-170 ° C.

The following amides were made using a similar procedure.
N- [2- (Dimethylamino) ethyl] -2-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20b)
Prepared from acid 18b and obtained (from acetonitrile) as a yellow plate (67%), mp 192-194 ° C.

N- [2- (Dimethylamino) ethyl] -2-butyl-6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20f)
Prepared from acid 18f and obtained as a yellow solid (89%), mp 127-128 ° C. [from light oil (bp 90-120 ° C.)].

N- [2- (Dimethylamino) ethyl] -2- (3-ethoxycarbonyl) propyl-6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide ( 20j)
Prepared from acid 18j with a reflux time of 5 hours and obtained as a yellow solid (74%), mp 130-132 ° C. (from toluene / light oil (bp 90-120 ° C.)).

Ｎ-[２-(ジメチルアミノ)エチル]-２-[２-(ジメチルアミノ)エチル]-１-オキソ-１,２-ジヒドロベンゾ[ｂ][１,６]ナフチリジン-４-カルボキサミド (２０ｌ)
酸１８ｌから調製し、そして黄色固体(８０％)、ｍｐ１４３〜１４４℃として、(トルエンから)得た。

N- [2- (dimethylamino) ethyl] -2- [2- (dimethylamino) ethyl] -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4- Carboxamide (20k)
Prepared from acid 18k and obtained as a yellow solid (84%), mp 141-143 ° C. [from light oil (bp 90-120 ° C.)].

N- [2- (Dimethylamino) ethyl] -2- [2- (dimethylamino) ethyl] -1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20 l)
Was prepared from the acid 18l, and a yellow solid (80%), as Mp143～144 ° C., it was obtained (from toluene).

(S) -N- [2- (Dimethylamino) ethyl] -6-methyl-1-oxo-2- (1-phenylethyl) -1,2-dihydrobenzo [b] [1,6] naphthyridine-4 -Carboxamide (20m)
Prepared from 18m acid and obtained as yellow semi-flowing material (86%).

N- [2- (Dimethylamino) ethyl] -6-methyl-2-phenyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20n)
Prepared from acid 18n and obtained as pale yellow needles (55%), mp 199-201 ° C. (from methanol).

N- [2- (Dimethylamino) ethyl] -2- (4-fluorophenyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20o )
Prepared from 18o and obtained from (acetonitrile) as pale yellow needles (88%), mp 219-220 ° C.

N- [2- (Dimethylamino) ethyl] -2- (3,4-dimethoxyphenyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20q)
Prepared from acid 18q and obtained as a yellow solid (92%), mp 199-201 ° C. (from toluene).

N- [2- (Dimethylamino) ethyl] -6-chloro-7-methoxy-2-methyl-1-oxo-1,2-dihydro-benzo [b] [1,6] naphthyridine-4-carboxamide (20x )
Prepared from acid 18w with reflux time of 5 hours and obtained as a brown solid (73%), mp 209-212 ° C. (from ace and nitrile).

N- [2- (Dimethylamino) ethyl] -7-methyl-6-oxo-6,7-dihydropyrido [2,3-b] [1,6] naphthyridine-9-carboxamide (20y)
Prepared from acid 18y with a reflux time of 1.5 hours (complete dissolution did not occur). The crude amide was added to a short silica column. The column is eluted first with dichloromethane / methanol (19: 1) and then with dichloromethane / methanol (1: 1) to give the amide as a yellow solid (17%), mp 218-221 ° C. (acetonitrile )

N- [2- (Dimethylamino) ethyl] -2-methyl-1-oxo-1,2-dihydropyrido [3,4-b] quinoxaline-4-carboxamide (20z)
Prepared from acid 18z with a reflux time of 45 minutes and obtained as golden flakes (47%), mp 215-218 ° C. (> 109 ° C. after needle formation) (from ace and nitrile).

The hydrochloride salt had mp 218-221 ° C. (derived from ethanol).
2,2 ′-[1,3-propanediylbis [(methylimino) -2,1-ethanediyl]] bis [N- (2- (dimethylamino) ethyl) -6-methyl-1-oxo-1,2 -Dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20aa)
Prepared from acid 18aa and obtained as a yellow solid (75%), mp 97-102 ° C. [from light oil (bp 90-120 ° C.)].

塩酸塩は、ｍｐ２７７〜２８０℃を有した(エタノール由来、黄色針状晶であった)。 (S) -N- [1-((Dimethylamino) carbonyl) ethyl] -2,6-dimethyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20bb )
Prepared from acid 18d with a reflux time of 45 minutes. To the residue from which thionyl chloride has been removed, triethylamine (2.2 mol equivalent) in dichloromethane is added followed by (S) -2-amino-N, N-dimethylpropionamide (1.1 mol equivalent) in dichloromethane. ) Was added. Standard reaction and operation gave the amide (88%) as yellow needles, mp 268-274 ° C. (from acetonitrile).

The hydrochloride salt had mp 277-280 ° C. (derived from ethanol, yellow needles).

塩酸塩は、ｍｐ２５１〜２５４℃、針状晶形成後＞２００℃(マスタード色粉末、アセトニトリル由来)を有した。 (S) -N- [2- (1-dimethylamino) propyl] -2,6-dimethyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20 cc)
Prepared from acid 18d with a reflux time of 45 minutes. A suspension of the residue in dichloromethane with the thionyl chloride removed was added to (S) -N ′, N′-dimethylpropane-1,2-diamine hydrochloride (2.2 mol equivalent) in dichloromethane. ) And triethylamine (2.2 mol equivalent) solution. Standard reaction and manipulation gave the amide (38%) as a light brown solid, mp 205-209 ° C. (from ace and nitrile).

The hydrochloride had mp 251-254 ° C.,> 200 ° C. (from mustard color powder, acetonitrile) after needle-like crystal formation.

N-[(2-Dimethylamino) ethyl] -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide perchlorate (20c)
Prepared from the 18c ammonium salt and obtained as a yellow solid (69%) in crude form. The perchlorate was prepared in ethanol, recrystallized from wet methanol and obtained as a brown solid, mp 218-219 ° C. (explosive degradation product> 250 ° C.).

Example 6 N- [2- (Dimethylamino) ethyl] -2-ethyl-6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] -naphthyridine-4-carboxamide (20e) Is an example of general method B of amide formation according to Preparation Scheme 2d.
A mixture of acid 18e (0.23 g, 0.81 mmol) and 1,1′-carbonyldiimidazole (CDI) (0.66 g, 4.07 mmol) in 1,4 dioxane (15 ml) was added under reflux. For 24 hours, during which dissolution occurred. The solvent was removed under reduced pressure and to the residue was added N, N-dimethylethylenediamine (1 ml) in dichloromethane (25 ml). The solution was stirred for 16 hours at room temperature. More dichloromethane was added and the solution was washed with 10% sodium hydroxide (x1) and washed with water (x3). The organic fraction was dried over magnesium sulfate and the solvent was removed under reduced pressure to give amide 20e as bright yellow (0.26 g, 91%), mp 157-158 ° C. (from acetonitrile).

The following compounds were prepared in a similar manner.
N- [2- (Dimethylamino) ethyl] -6-methyl-1-oxo-2- (2,2,2-trifluoroethyl) -1,2-dihydrobenzo [b] [1,6] naphthyridine 4-Carboxamide (20g)
Prepared from 18 g of acid and obtained (from acetonitrile) as a yellow solid (83%), mp 227-230 ° C.

N- [2- (Dimethylamino) ethyl] -2- (ethoxycarbonylmethyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] -naphthyridine-4-carboxamide (20i )
Prepared from acid 18i with a reflux time of 48 hours and refilling with an equal amount of CDI after 24 hours and obtained as a yellow solid, mp 214-215 ° C. (from acetonitrile).

N- [2- (Dimethylamino) ethyl] -2- (4-boronophenyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20p)
Prepared from acid 18p in a nitrogen atmosphere with a reflux time of 48 hours and a refill of an equal amount of CDI after 24 hours. When the ammonia saturation reaction is complete, the volatiles are removed by heating under reduced pressure (˜0.3 mmHg, 100 ° C., 20 minutes) and the residual N, N-dimethylethylenediamine is azeotropically distilled with toluene. (× 3). The residue was then boiled in toluene and decanted from brown oil while hot. Toluene is removed under reduced pressure and the residue is recrystallized from acetonitrile to yield the intermediate N- [2- (dimethylamino) ethyl] -6-methyl-1-oxo-2- [4- (4,4, 5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] 1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide as a yellow solid (74%), mp139 Obtained as ~ 141 ° C.

Water (5 ml) was added to a solution of the compound (0.12 g, 0.23 mmol) in methanol (5 ml) and the whole was heated under reflux for 30 minutes. Reduce the volume to about 2 ml under reduced pressure, add water and filter the solid, wash with water and recrystallize from ethanol to give 20p of boric acid as a yellow solid (0.05 g, 49%), mp 242-244 ° C.

N- [2- (Dimethylamino) ethyl] -2- (3,4-dimethoxybenzyl) -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (20r)
Prepared from acid 18r with a reflux time of 48 hours, and refilling with an equal volume of CDI after 24 hours, and obtained from yellow acetonitrile (85%), mp 213-214 ° C. (acetonitrile).

N- [2- (Dimethylamino) ethyl] -2- [2- (3,4-dimethoxy-phenyl) ethyl] -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6 ] Naphthyridine-4-carboxamide (20s)
Prepared from acid 18s with a reflux time of 48 hours and refilling with an equal amount of CDI after 24 hours and obtained as a yellow solid (81%), mp 113-114 ° C. (from acetonitrile).

N- [2- (Dimethylamino) ethyl] -6-methyl-2- (pyridin-2-yl) methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] -naphthyridine-4- Carboxamide (20t)
Prepared from acid 18t by refluxing for 48 hours and recharging with an equal amount of CDI after 24 hours and obtained as a bright yellow solid (75%), mp 183-184 ° C. (from acetonitrile).

N- [2- (Dimethylamino) ethyl] -6-methyl-1-oxo-2- [3- (2-oxopyrrolidin-1-yl) pyropyl] -1,2-dihydrobenzo [b] [1, 6] -Naphthyridine-4-carboxamide (20u)
Prepared from acid 18u with a reduction time of 24 hours and obtained as a yellow solid (89%), mp 170-171 ° C. (from acetonitrile).

N- [2- (Dimethylamino) ethyl] -7-methoxy-2-methyl-1-oxo-1,2-dihydro-benzo [b] [1,6] naphthyridine-4-carboxamide (20w)
Prepared from acid 18w with 96 hours reflux time and refilling with an equal amount of CDI after 48 hours and obtained as a yellow solid (80%), mp 213-215 ° C. (from acetonitrile).

N- [2- (dimethylamino) ethyl] -2-[((2- (dimethylamino) ethyl) amino) carbonyloxy] ethyl-6-methyl-1-oxo-1,2-dihydrobenzo [b] [ 1,6] naphthyridine-4-carboxamide (21a)
Prepared from acid 18h with a reflux time of 48 hours and obtained as a yellow solid (63%), mp 75-76 ° C. (from toluene) (× 3).

N- [2- (dimethylamino) ethyl] -2- [N-(((2- (dimethylamino) ethyl) amino) carbonyl) -1H-indol-3-yl] ethyl-6-methyl-1-oxo -1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide (21b)
Prepared from acid 18v by refluxing for 48 hours and refilling with equal CDI after 24 hours and obtained as a yellow solid (62%), mp 182-185 ° C. (from acetonitrile).

Example 7 N- [2- (Dimethylamino) ethyl] -2-hydroxyethyl-6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6] -naphthyridine-4-carboxamide (20h Is a hydrolyzable modification of the disubstituent in 4-carboxamide according to Preparation Scheme 2e.
To carbamate 21a (0.55 g, 1.49 mmol) in ethanol (25 ml) was added 10% sodium hydroxide (20 ml) and the whole was heated at reflux for 1 hour, then cooled on ice and concentrated hydrochloric acid. To pH 8. It was then evaporated to dryness under reduced pressure. The residual solid was boiled in acetonitrile, the mixture was filtered while hot, and the filtrate was dried under reduced pressure to give an orange solid (0.26 g). The solid was dissolved in a small amount of warm ethanol and added to a bed of silica. This was eluted with a small amount of ethanol followed by ethanol / triethylamine (25: 1). The ethanol / triethylamine eluate was dried under reduced pressure. The residual solid (0.17 g) was dissolved in a small amount of chloroform, filtered through a bed of basic alumina, washed with chloroform and subsequently eluted with methanol. The methanol eluate was evaporated to dryness under reduced pressure to give a yellow solid (0.12 g). The solid was recrystallized twice from dichloromethane to give amide 20h as a yellow solid (0.10 g, 24%), mp 174-180 ° C.

The filtrate from the chloroform wash was evaporated to dryness under reduced pressure to give 2- (2- (dimethylamino) ethyl) -4-[(2- (dimethylamino) ethylamino) methylene] -6-methyl-4H. -Benzo [b] [1,6] naphthyridine-1,3-dione (22) was obtained as a yellow solid (0.04 g, 9%), mp 202-206 ° C.

The following modifications were made in a similar manner (Scheme 2f):
N- [2- (Dimethylamino) ethyl] -2- [2- (1H-indol-3-yl) ethyl] -6-methyl-1-oxo-1,2-dihydrobenzo [b] [1,6 ] Naphthyridine-4-carboxamide (20v)
To a hot solution of bisamide 21b (0.58 g, 1.00 mmol) in ethanol (10 ml) was added 10% sodium hydroxide (10 ml) and the whole was heated at reflux for 40 minutes. The reaction mixture is then evaporated to dryness under reduced pressure, water is added and the solid is filtered and washed with water to give 20v as a golden solid (0.42 g, 90%), mp 105-107 ° C. Obtained (from acetonitrile).

Example 8 In Vitro Antitumor Activity The compounds identified in Table 1 measured mouse p388 leukemia cells, Lewis lung carcinoma cells (LLTC), and human Jurkat leukemia by measuring IC ₅₀ values. cells (Jurkat leukemia cells (JLc)) , were evaluated for growth inhibition properties for that amsacrine and doxorubicin-resistant induced cell (JL _a and JL _D). the induced cells may be obtained as previously described and cultured (Finlay et al., 1990; 1994) Growth inhibition assays were performed by culturing cells in microculture plates (150 μL / well) as follows.
P388: 4.5 × 10 ³ cells / well; 3 days LLTC: 1 × 10 ³ cells / well; 04 Jurkat cell lines: 3.75 × 10 ³ cells / well; 04 cell proliferation, ^[3 H ] -Thymidine incorporation (P388) (Marshall et al., 1992) or sulforhodamine assay (Skehan et al., 1990). Independent assays were performed twice using doxorubicin, etoposide, camptothecin, and DACA as reference compounds. The results are summarized in Table 2.

footnote
^a IC ₅₀ ; drug concentration that reduces cell number to 50% of control culture
^b JL _c IC ₅₀ values of Jurkat cell lines JL _A and JL _D for (text references)
^c Mouse P388 leukemia cells
^d Mouse Lewis lung cancer cells
^eHuman Jurkat leukemia cells
^f R = CH ₂ CH ₂ NMe ₂
^g Bis compound, example of formula II
^h R = (S) —CH (Me) CONMe ₂
ⁱ R = (S) -CH (Me) CH ₂ NMe ₂

JL _A cell line is resistant to DNA inter cullet type amsacrine and similar agents. This is because the level of Topo II enzyme is reduced. JL _D cell line is resistant to doxorubicin. It is mainly due to the altered level of Topo II, but probably through additional mechanisms. The ratio between the IC ₅₀ value of the parent cell line drug and the IC ₅₀ value of the sub lineage, ie ((IC ₅₀ [JL _A ] / IC ₅₀ [JL _C ] and (IC ₅₀ [JL _D ] / IC ₅₀ [JL _C ]) therefore provides some indication of the mechanism of cytotoxicity: classical topo II inhibitors such as amsacrine, doxorubicin, and etoposide have a high ratio (10-90 fold), while I inhibitors, such as mixed inhibitors of camptothecin and topo I / II, such as DACA (4), have a ratio of about 2 times, and values of these ratios of less than about 1.5-2 are non-topo II mediated. Suggests cytotoxicity by sexual mechanism.

Example 9: In vivo anti-tumor active compound 20d was evaluated against murine clolon 38 tumors implanted subcutaneously in C57BL / 6 mice. The advanced colorectal 38 tumor model is fairly refractory with standard clinical topo II drugs and antimetabolites and alkylating agents. To date, an in vivo model using the colon 38 tumor model has been shown to be the best indicator of clinical utility (Goldin, A, 1980). The model therefore represents a good test for in vivo activity.

Colon 38 tumors grew subcutaneously from 1 mm ³ pieces implanted on one flank of C57 / BL mice (anesthetized with 90 mg / kg pentobarbital). When tumors reached a diameter of approximately 4 mm (7-8 days), mice were divided into control and drug-treated groups (5 / group) to have comparable mean tumor volumes in each group. The drug was administered as an aqueous hydrochloride solution in distilled water and injected in a volume of 0.01 ml / g (body weight). Mice treated with prior art compounds, doxorubicin, daunorubicin, amsacrine, mitoxantrone, DACA, etoposide, or irinotecan were used as positive controls. Mice were closely monitored and tumor diameter was measured 3 times a week with calipers. Tumor volume was calculated as 0.52 × a ² × b. Where a and b are the short and long axes, and the data was plotted on a semilogarithmic graph as mean accommodation volume (SEM) versus time after treatment. The results at 20d are shown in FIG. 3 and are summarized in Table 3 for all compounds. Growth delay was calculated as the time the tumor reached an average volume four times its pre-treatment volume.

^a ｑ２ｄ×２＝２日おき×２； ｑ４ｄ×３＝４日おき×３；
ｑ７ｄ×２＝７日おき×２； ｓ.ｄ.＝一回投与
^b 処置の開始後２０日において計測できる腫瘍を持たないマウスの数/全マウス数
^c 毒性の証拠を提供しない最大投与量

^a q2d × 2 = 2 every 2 days × 2; q4d × 3 = every 4 days × 3;
q7d × 2 = every 7 days × 2; sd = single administration
^b Number of mice without tumor / total number of mice that can be measured 20 days after the start of treatment
^c Maximum dose that does not provide evidence of toxicity

Of the prior art compounds tested, only doxorubicin, irinotecan, and DACA resulted in a significant delay in growth of colon 38 tumors, and none of them resulted in long-term survival. It is clear from However, a single dose of Compound 20d resulted in growth retardation in at least 20 days in all but the lowest dose. In this case, the treated mice survived for a long time and no tumor was present 60 days after the end of treatment. Theoretically, the period was long enough for one viable cell to re-form the tumor, so these mice would certainly have a normal life span if maintained for a long enough period. Let's go.

Example 10: In vivo anti-tumor active compound 20d was evaluated against human melanoma xenografts and given 30 days at two doses of 5.9 mg / kg for 7 days. Tumor growth was delayed. The NZM4 melanoma cell line (Marshall et al., 1994) was cultured and grown, and 1 × 10 ⁷ cells were implanted subcutaneously on one flank of athymic (nude) mice. When tumors reached a diameter of approximately 6 mm (15 days), mice were divided into control and drug treatment groups (5 mice / group) so that each group had similar average tumor volumes. The drug was administered as a hydrochloride solution in distilled water and injected in a volume of 0.01 ml / (body weight) g. Mice were closely monitored and tumor diameter was measured twice a week with a capillary. Tumor volume was calculated as 0.52 × a ² × b. Here, a and b are the short and long axes of the tumor, and the data was plotted as mean tumor volume (± SEM) versus time after treatment on a semilogarithmic graph. The result of 20d is shown in FIG. Growth delay was calculated as the time for the tumor to reach an average volume of three times the untreated volume.

Discussion These results indicated that the compounds of the present invention have cytotoxic activity against animal and human tumor cell lines and are active against transplanted tumors in mice. Thus, these compounds have potential utility as anticancer agents.

  It will be appreciated by those skilled in the art that, when broadly described, many variations and / or modifications may be made to the invention shown in the specific embodiments without departing from the spirit or scope of the invention. . It should be considered that this aspect is therefore exemplary and not restrictive in all respects.

References cited herein are described below and are incorporated herein.

FIG. 1 shows the structures of prior art compounds 1-15 referenced herein. The reaction scheme for preparing the compounds of Table 1 is shown. Scheme 2a: 4H-pyrano [4,3-b] quinoline-1,3-dione route; Scheme 2b: reaction with amines. The reaction scheme for preparing the compounds of Table 1 is shown. Scheme 2c: Reaction with 3,4 dimethoxyaniline; Scheme 2d: Preparation of carboxamide. The reaction scheme for preparing the compounds of Table 1 is shown. Scheme 2e and 2f—Preparation of intermediate bis amide and its hydrolysis to mono amide. FIG. 3 shows the growth of large intestine 38 tumors implanted in control mice (●) and tumor growth in mice that received 20d administration (8.9 mg / kg; ◯) (3.9 mg / kg; Δ) once. It is a graph which shows the comparison with. FIG. 4 shows growth of the NZM4 melanoma cell line implanted subcutaneously in control mice (●) and tumor growth (Δ) in mice receiving 20d two doses (5.9 mg / kg) 7 days apart. It is a graph which shows comparison of these.

Claims (29)

The following formula I:

{Where,
The position numbers noted refer to the positions illustrated above, and one or more W and one or more Z are bonded to one ring carbon, or any of the 3, 4, and 6-10 positions. Bond to multiple ring carbons at the position
here,
Q is O or S;
W is C (= Q) NR-M- (CH ₂ ) _m R ¹
(In the group,
M is CHJ or G;
R is H or an optionally substituted C _1-4 alkyl group;
J is H or an optionally substituted C ₁ -C ₆ alkyl group;
G is an optionally substituted fully saturated or partially unsaturated carbocyclic or heterocyclic ring, or an aromatic carbocyclic or heterocyclic ring;
R ¹ is C (= NR ² ) NH ₂ , NHC (= NR ³ ) NH ₂ , or NR ⁴ R ⁵ ;
here,
Each of R ² and R ³ is independently H or an optionally substituted C _1-4 alkyl group;
R ⁴ and R ⁵ are independently H or an optionally substituted C _1-4 alkyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are optionally substituted Forming a saturated or unsaturated heterocyclic group, and
m is an integer of 0-6. );
Y is H, C _1-6 alkyl or (CH ₂ ) _n —X— (CH ₂ ) _p U
(In the group,
X is CH2 _, C = O, CH = CH, O, S, NR or G;
n and p are integers from 0 to 6, and
U is H, CF ₃ , halo, NR ⁴ R ⁵ , ⁺ NRR ⁴ R ⁵ , cyano, C (═O) NR ⁴ R ⁵ , OR ⁴ , CO ₂ R ⁴ , G, NR ⁴ G, or OG Is); and
Z is H, halo, OH, CO ₂ H, CO ₂ R ⁴ , SO ₂ R ⁴ , NR ⁴ R ⁵ , nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, A C _1-6 haloalkoxy, a C _1-6 aminoalkyl, a C _1-6 aminoalkoxy, or an aza functional group that replaces a CH functional group, or a bridge at the 6-7, 7-8, or 8-9 position; As a result, the compound is a carbon or carbon / nitrogen skeleton that forms a 5- or 6-membered fused carbocyclic or heterocyclic ring, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvent Japanese compounds, pharmaceutically acceptable derivatives, prodrugs, tautomers and / or isomers thereof. ^{R, R 2, R 3,} R 4, and the optional substituents for R ^5, is one or more OH or NH ₂ groups, the compounds according to claim 1. It said optional substituents for J is, one or more OH, OMe, NH _2, NHMe, or NMe a ₂ group, the compound according to claim 1 or claim 2. Said substituent for G is one or more of halo, OH, CO ₂ H, NR ⁴ R ⁵ , NRSO ₂ R, SO ₂ NR ⁴ R ⁵ , nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 aminoalkyl, C _1-6 aminoalkoxy, or B (OR ⁶ ) (OR ⁷ ) (wherein R ⁶ and R ⁷ are independently Hydrogen or optionally substituted C _1-4 alkyl groups, or together with the O and B atoms to which they are attached form an optionally substituted fully saturated or partially unsaturated heterocycle The compound according to any one of claims 1 to 3, wherein Q is O; W is CONH (CH ₂ ) ₂ N (CH ₃ ) ₂ or CONHCH (CH ₃ ) CH ₂ N (CH ₃ ) ₂ ; Y is methyl, butyl, or methoxy-substituted phenyl And the compound according to any one of claims 1 to 4, wherein Z is H, Cl, methyl, or methoxy.   The compound is N- [2- (dimethylamino) ethyl] -2,6-dimethyl-1-oxo-1,2-dihydrobenzo [b] [1,6] naphthyridine-4-carboxamide, or pharmaceutically acceptable 6. A compound according to any one of claims 1 to 5, which is a salt or N-oxide thereof. Formula II or Formula III below:

{Where,
In Formula II, one or more W and one or more Z, and in Formula III, one or more Z and C (= Q) NR are one of the ring carbons or any of the positions 3, 4, and 6-10. Bond to multiple ring carbons with
here,
Q, R, W, Y, and Z are as defined in formula I according to any one of claims 1-6;
x is an integer from 2 to 4 and
L is a linker group having a valence x}, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, pharmaceutically acceptable derivative, prodrug, Mutant and / or isomers.   8. A compound according to claim 7, wherein x is 2. L is O; S; optionally substituted with one or more optionally substituted aryl or optionally substituted heterocyclic groups, and / or optionally dispersed with one or more O, S, or N atoms, optionally substituted 9. A compound according to claim 7 or claim 8 which is a _C1-20 alkylene, alkenylene, or alkynylene chain; or an optionally substituted saturated or unsaturated aryl or heterocyclic group.   The compound according to any one of claims 7 to 9, wherein L is a linker group containing nitrogen. L is V ¹ -[(CHR) _q NR ⁴ ] _r (CHR) _q -V ²
(In the group,
V ¹ and V ² are each independently oxygen, NR ⁴ , or CHR;
q is an integer from 0 to 5 optionally having different values for each subunit of linker L;
r is an integer from 0 to 2,
R ⁴ is as defined in formula I according to any one of claims 1 to 6 or when r is greater than 0, R and R ⁴ together are optionally substituted. The compound according to any one of claims 7 to 10, wherein the branched or linear alkylene is formed. R and R ⁴ are each independently H, CH ₃ , or C ₂ H ₅ , or when r is greater than 0, R and R ⁴ are —CH ₂ CH ₂ CH ₂ —. 11. The compound according to 11. L is the following:
-(CH ₂ ) ₂ NH (CH ₂ ) _2-
-(CH ₂ ) ₃ -NMe- (CH ₂ ) _3-
-(CH ₂ ) ₂ NH (CH ₂ ) ₂ NH (CH ₂ ) _2-
-(CH ₂ ) ₂ NH (CH ₂ ) ₃ NH (CH ₂ ) _2-
-(CH ₂ ) ₂ NMe (CH ₂ ) ₂ NMe (CH ₂ ) _2-
-(CH ₂ ) ₂ NMe (CH ₂ ) ₃ NMe (CH ₂ ) _2-
-N, N'-bis (ethylene) piperazine-
-N, N'-bis (propylene) piperazine-
-(CH ₂ ) _S NH (CH ₂ ) _t-
-(CH ₂ ) _S N alkyl (CH ₂ ) <sub>t-
- (CH 2) S NH (</sub> CH 2) t NH (CH 2) u -, and
-(CH ₂ ) _S N alkyl (CH ₂ ) _t N alkyl (CH ₂ ) _U-
The compound according to any one of claims 7 to 12, wherein s, t, and u are an integer of 2 to 6. Formula IV below:

{Where,
One or more Z and one or more CO ₂ H groups are bonded to one of the ring carbons or to a plurality of ring carbons at any of the 3, 4, and 6-10 positions; and Q, Y, and Z is as defined in Formula I. A compound of formula I according to any one of claims 1 to 6, or any one of claims 7 to 13, comprising converting a compound of formula I into an amide of formula I, II or III A process for producing a compound of formula II or III according to claim 1.   15. The method of claim 14, wherein the converting step comprises an intermediate step of converting a compound of formula IV to an imidazolide and then reacting with a suitable amine to give an amide of formula I, II, or III. .   15. The method of claim 14, wherein the carboxylic acid of formula IV is converted to an acid halide and subsequently reacted with an amine to give an amide of formula I, II, or III.   A compound of formula I according to any one of claims 1 to 6 or a compound of formula II or III according to any one of claims 7 to 13 with a pharmaceutically or veterinary acceptable carrier. A pharmaceutical or veterinary pharmaceutical composition comprising the combination.   A therapeutically effective amount of a compound of formula I according to any one of claims 1-6 or a compound of formula II or III according to any one of claims 7-13 to a subject in need thereof. A method of treating and / or preventing a cell proliferative disease, comprising administering.   The method of claim 18, wherein the cell proliferative disorder is a neoplasm, tumor, or cancer.   The cell proliferative disorder is breast, lung, prostate, kidney, skin, nerve, ovary, uterus, liver, pancreas, epithelium, stomach, intestine, exocrine, endocrine cancer, lymph, hematopoietic system, and / or head and neck 20. The method of claim 18 or claim 19, wherein the method is tissue cancer.   21. The cell proliferation disease according to any one of claims 18 to 20, wherein the cell proliferative disorder is leukemia, lymphoma, multiple myeloma, sarcoma, brain tumor or lung, breast, ovary, testis, and / or colon cancer. the method of.   23. The method of any one of claims 18-21, wherein the compound of formula I, II, or III is administered separately from other drugs, over time, or simultaneously.   23. The method of claim 22, wherein the drug is an anti-neoplastic agent, a second DNA binding anti-cancer therapeutic agent, and / or a side effect reducing agent.   24. The compound of any one of claims 18-23, wherein the compound of formula I, II, or III is administered in the form of a tumor activating prodrug, wherein the compound binds to a trigger domain. the method of.   A compound of formula I according to any one of claims 1 to 6 or a compound of formula II according to any one of claims 7 to 13 in the manufacture of a medicament for the treatment and / or prevention of cell proliferative diseases. Use of compounds of III.   14. A compound of formula I according to any one of claims 1 to 6 or a formula II according to any one of claims 7 to 13 intended for use in the treatment and / or prevention of cell proliferative disorders. Or a compound of II.   14. A compound of formula I according to any one of claims 1 to 6 or any one of claims 7 to 13 as cytotoxic, anti-neoplastic, anti-tumor and / or anti-cancer agent. Use of a compound of formula II or II When Z is attached to a ring carbon in it and 6-position is CH _3, CO ₂ H is attached to a ring carbon at position 4, and Q is O, and Y is not a CH _3, Claim 14 A compound of formula IV Q is O, and CO ₂ H is attached to the 4-position, a process for preparing a compound of formula IV according to claim 28,
The following formula V:

{Where,
Z is as defined in formula I as defined in any one of claims 1 to 6} YNH ₂ (wherein Y is as defined in formula I). ).

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